The invention relates to bicyclic and tricyclic xcex2-lactams and their pharmaceutically compatible salts.
The present invention is concerned with compounds having the formula 
in which R signifies lower alkoxycarbonyl, lower alkoxy-carbonylamino, the acyl residue of an xcex1- or xcex2-amino acid or a residue of the formula
Qxe2x80x94Xxe2x80x94Yxe2x80x94xe2x80x83xe2x80x83(a)
wherein Q signifies a 3- to 6-membered ring which optionally contains nitrogen, sulphur and/or oxygen and which is optionally bonded with a fused ring, X signifies a direct bond or a linear xe2x80x9cspacerxe2x80x9d with up to 6 atoms consisting of carbon, nitrogen, oxygen and/or sulphur, of which up to 2 atoms can be nitrogen atoms and 1 atom can be oxygen or sulphur, and Y represents one of the groups xe2x80x94COxe2x80x94, xe2x80x94CSxe2x80x94, xe2x80x94CONHxe2x80x94 and (where X contains neither sulphur nor carbonyl as a terminal component) xe2x80x94SO2xe2x80x94; and in which R1 signifies hydrogen, halogen, carbamoyloxy, lower alkanoyloxy or a group of the formula xe2x80x94Sxe2x80x94Het, wherein Het represents a 5- or 6-membered heteroaromatic group containing nitrogen, sulphur and/or oxygen, and R2 represents the sulpho group xe2x80x94SO3H or R1 and R2 together signify a group of the formula, 
wherein A represents hydrogen or a residue which is usable in the 3-position of cephalosporin antibiotics, and in which R3 represents hydrogen or R1 and R3 together represent a group of the formula
xe2x95x90CHxe2x80x94Raxe2x80x83xe2x80x83(c)
wherein Ra signifies one of the groups
xe2x80x94CORbxe2x80x83xe2x80x83(c1)
xe2x80x94CH2xe2x80x94OCORcxe2x80x83xe2x80x83(c2)
xe2x80x94CH2xe2x80x94NRdRexe2x80x83xe2x80x83(c3)
xe2x80x83xe2x80x94CH2xe2x80x94Sxe2x80x94Hetxe2x80x83xe2x80x83(C4)
in which Rb represents lower alkoxy or amino, Rc represents lower alkyl, phenyl or amino, Rd and Re each independently represent hydrogen or lower alkyl or Rd and Re together with the N atom to which they are attached represent a 5- or 6-membered N-heterocycle which optionally contains a further nitrogen, oxygen or sulphur atom and Het represents a 5- or 6-membered heteroaromatic group containing nitrogen, sulphur and/or oxygen,
and pharmaceutically compatible salts of these compounds.
These compounds are novel and are distinguished by therapeutically valuable properties. In particular, they have pronounced xcex2-lactamase inhibiting properties and are accordingly useful in combination with xcex2-lactam antibiotics such as the penicillins and cephalosporins in the control of pathogens which form xcex2-lactamase.
The present invention is concerned with compounds having the formula 
in which R signifies lower alkoxycarbonyl, lower alkoxy-carbonylamino, the acyl residue of an xcex1- or xcex2-amino acid or a residue of the formula
Qxe2x80x94Xxe2x80x94Yxe2x80x94xe2x80x83xe2x80x83(a)
wherein Q signifies a 3- to 6-membered ring which optionally contains nitrogen, sulphur and/or oxygen and which is optionally bonded with a fused ring, X signifies a direct bond or a linear xe2x80x9cspacerxe2x80x9d with up to 6 atoms consisting of carbon, nitrogen, oxygen and/or sulphur, of which up to 2 atoms can be nitrogen atoms and 1 atom can be oxygen or sulphur, and Y represents one of the groups xe2x80x94COxe2x80x94, xe2x80x94CSxe2x80x94, xe2x80x94CONHxe2x80x94 and (where X contains neither sulphur nor carbonyl as a terminal component) xe2x80x94SO2xe2x80x94; and in which R1 signifies hydrogen, halogen, carbamoyloxy, lower alkanoyloxy or a group of the formula xe2x80x94Sxe2x80x94Het, wherein Het represents a 5- or 6-membered heteroaromatic group containing nitrogen, sulphur and/or oxygen, and R2 represents the sulpho group xe2x80x94SO3H or R1 and R2 together signify a group of the formula 
wherein A represents hydrogen or a residue which is usable in the 3-position of cephalosporin antibiotics, and in which R3 represents hydrogen or R1 and R3 together represent a group of the formula
xe2x95x90CHxe2x80x94Raxe2x80x83xe2x80x83(c)
wherein Ra signifies one of the groups
xe2x80x94CORbxe2x80x83xe2x80x83(c1)
xe2x80x94CH2xe2x80x94CORcxe2x80x83xe2x80x83(c2)
xe2x80x94CH2xe2x80x94NRdRexe2x80x83xe2x80x83(c3)
xe2x80x94CH2xe2x80x94Sxe2x80x94Hetxe2x80x83xe2x80x83(c4)
in which Rb represents lower alkoxy or amino, Rc represents lower alkyl, phenyl or amino, Rd and Re each independently represent hydrogen or lower alkyl or Rd and Re together with the N atom to which they are attached represent a 5- or 6-membered N-heterocycle which optionally contains a further nitrogen,
oxygen or sulphur atom and Het represents a 5- or 6-membered heteroaromatic group containing nitrogen, sulphur and/or oxygen, and pharmaceutically compatible salts of these compounds.
These compounds are novel and are distinguished by therapeutically valuable properties. In particular, they have pronounced xcex2-lactamase inhibiting properties and are accordingly useful in combination with xcex2-lactam antibiotics such as the penicillins and cephalosporins in the control of pathogens which form xcex2-lactamase. Those of ordinary skill in the art will appreciate that xcex2-lactamase inhibitors possess the ability to inactivate xcex2-lactamase by blocking the sites of these enzymes.
The term xe2x80x9clower alkylxe2x80x9d taken alone or in combinations such as xe2x80x9clower alkoxyxe2x80x9d, xe2x80x9clower alkylthioxe2x80x9d, xe2x80x9clower alkylsulphinylxe2x80x9d, xe2x80x9clower alkylsulphonylxe2x80x9d, xe2x80x9clower alkoxycarbonylxe2x80x9d, xe2x80x9calkanoyloxyxe2x80x9d and the like signifies straight-chain or branched saturated hydrocarbon residues with a maximum of 7, preferably a maximum of 4, carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl and the like. xe2x80x9cHalogenxe2x80x9d signifies all four halogens, viz., bromine, chlorine, fluorine, and iodine, but preferably chlorine or fluorine. xe2x80x9cAminoxe2x80x9d can also be substituted, for example, by lower alkyl, such as methylamino and dimethylamino. xe2x80x9c5- or 6-membered N-heterocycle optionally contains a further nitrogen, oxygen or sulphur atomxe2x80x9d can also be N- or C-substituted, for example, by lower alkyl. Examples of saturated heterocycles include pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl and thiomorpholinyl. Examples of aromatic heterocycles include residues which are derived from pyridine and (xcex1, xcex2 or xcex3)-picoline, whereby a positive charge exists on the nitrogen atom (xe2x80x9czwitterionxe2x80x9d). The term xe2x80x9cHetxe2x80x9d stands for a 5- or 6-membered heteroaromatic group such as for example, tetrazolyl, methyltetrazolyl, methylthiozolyl.
The R groups present in the compounds of formula I have the following significances a), b), c) and d):
a) Lower alkoxycarbonyl such as for example, methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl.
b) Lower alkoxycarbonylamino such as for example, methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino.
c) The acyl residue of an xcex1- or xcex2-amino acid, which can be not only a natural amino acid, such as, for example, alanine, arginine, asparagine, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine, but also a non-natural amino acid, such as for example, an acyl group derived from xcex2-alanine, ornithine, cystine, 3-hydroxyproline, 4-hydroxyproline, sarcosine, 2-(2-thienyl)-glycine, 2-(2-amino-4-thiazolyl)-glycine, 2-phenylglycine, p-hydroxyphenylglycine, m-hydroxyphenylglycine, o-fluorophenylglycine, m,p-dihydroxyphenylglycine or xcex1-aminocinnamic acid. The amino group can optionally be substituted, for example, by lower alkyl such as methyl or ethyl, by aryl, especially by phenyl (as in N-phenylglycyl), by acyl, especially by lower alkanoyl such as acetyl or propionyl, by benzoyl, benzyloxycarbonyl, t-butoxycarbonyl or N-heterocyclylcarbonyl such as (4-ethyl-2,3-dioxo-1-piperazinyl)-carbonyl or (4-hydroxy-6-methyl-3-pyridyl)-carbonyl. Of the acyl residues of xcex1- and xcex2-amino acids those which are derived from an xcex1-amino acid are preferred.
d) A residue of the formula
Qxe2x80x94Xxe2x80x94Yxe2x80x94xe2x80x83xe2x80x83(a)
wherein Q, X and Y are defined above.
Q preferably signifies a 5- or 6-membered (hetero)aromatic ring which optionally contains nitrogen, sulphur and/or oxygen and which is optionally bonded with a further fused ring. Heteroaromatic rings generally contain 1-4 nitrogen atoms and/or 1-2 sulphur or oxygen atoms. Examples of (hetero)aromatic rings for Q include: 2-furyl, 3-furyl, thiazolyl, thiadiazolyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl (for example, 1H-tetrazol-5-yl and 1H-tetrazol-1-yl), pyrazinyl, pyridazinyl and pyrimidinyl. The Q groups can also be substituted, for example, by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, sulphonyloxy, halogen, amino, dimethylamino or chloroacetylamino, for example, 4-tolyl, 3-methyl-(2-furyloxy), 1-methyl-1H-tetrazol-5-yl, 4-hydroxyphenyl, 4-anisyl, 3,4,5-trimethoxyphenyl, 4-chlorophenyl, 4-fluoro-(2-pyridyl), 2-amino-4-thiazolyl, 5-methyl-1,3,4-thiadiazol-2-yl, p-amino-phenyl, p-(chloroacetylamino)-phenyl, 3,4-disulphonyloxy-phenyl and 3,4-diacetoxyphenyl. A further ring can be fused on, especially a phenyl ring such as for example, in indolyl, 1H-benzotriazol-1-yl, or also a 5- or 6-membered heterocycle such as for example, in benzimidazol-5-yl 2-oxo-2H-1-benzopyran-7-yl, 2-oxo-4-(trifluoromethyl)-2H-1-benzopyran-7-yl, or 1H-benzotriazol-5-yl.
Those of ordinary skill in the art will appreciate that when Q signifies a 5- or 6-membered (hetero)aromatic ring which optionally contains nitrogen, sulphur, and/or oxygen, if Q does not contain nitrogen, sulphur and/or oxygen, then Q contains all carbon atoms and is a 5- or 6-membered aromatic ring. Examples include cyclopentadienyl anion and phenyl. If Q contains nitrogen, sulphur, and/or oxygen, then those of ordinary skill in the art will appreciate that Q would then signify a 5- or 6-membered heteroaromatic ring, examples of which are set forth above.
Q can, however, also signify a 3- to 6-membered (hetero)-saturated ring which optionally contains nitrogen, sulphur and/or oxygen. Heterocyclic rings generally contain 1-4 nitrogen atoms and/or 1-2 sulphur or oxygen atoms. Examples of (hetero)saturated rings Q include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl and tetrahydrofuryl. These groups can also be substituted, for example, by lower alkyl, oxo etc., for example, 4-methyl-1-piperazinyl and 2-oxo-3-tetrahydro-thienyl.
Those of ordinary skill in the art will appreciate that when Q signifies a 3- to 6-membered (hetero)saturated ring which optionally contains nitrogen, sulphur and/or oxygen, if Q does not contain nitrogen, sulphur and/or oxygen, then Q contains all carbon atoms and is a 3- to 6-membered saturated ring, examples of which are set forth above. If Q contains nitrogen, sulphur, and/or oxygen, then those of ordinary skill in the art will appreciate that Q would then signify a 3- to 6-membered heterosaturated ring, examples of which are set forth above.
The xe2x80x9cspacerxe2x80x9d X present in the residue (a) of the formula Qxe2x80x94Xxe2x80x94Yxe2x80x94 can consist for example, of 1-6 carbon atoms, of 1 nitrogen atom and 0-5 carbon atoms, of 2 nitrogen atoms and atom and 0-5 carbon atoms or of 1 sulphur atom and 0-5 carbon atoms and other combinations known to those in the art. In the xe2x80x9cspacerxe2x80x9d a carbon atom can appear as a keto group (CO) and a sulphur atom present can appear as a sulphonyl group (SO2). A carbon atom in the xe2x80x9cspacerxe2x80x9d can be substituted, for example, by hydroxy, carboxy, sulphonyloxy, carbamoyloxy or C1-C4 alkyl such as methyl, ethyl or isopropyl. Examples of xe2x80x9cspacersxe2x80x9d falling under X include:
xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2NHxe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94SO2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94NHxe2x80x94; xe2x80x94CH2xe2x80x94Oxe2x80x94NHxe2x80x94COxe2x80x94CH2CH2xe2x80x94, xe2x80x94CHOHxe2x80x94, xe2x80x94CH(COOH)xe2x80x94, xe2x80x94CH(OSO3H)xe2x80x94, xe2x80x94CH(OCONH2)xe2x80x94, xe2x80x94CH[CH(CH3)2]xe2x80x94.
Preferred xe2x80x9cspacersxe2x80x9d are: xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94NHxe2x80x94 and xe2x80x94CH2NHxe2x80x94.
When Y represents the xe2x80x94SO2xe2x80x94 group, X can contain neither sulphur nor a carbonyl group as a terminal component. In other words, the xe2x80x94SO2xe2x80x94 group cannot be linked directly with a sulphur atom or with a sulphonyl group or a carbonyl group. Examples of xe2x80x9cspacersxe2x80x9d X which can be linked with Y when it signifies xe2x80x94SO2xe2x80x94 include:
xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2NHxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94NHxe2x80x94, xe2x80x94CHOHxe2x80x94, xe2x80x94CH[CH(CH3)2].
Preferred xe2x80x9cspacersxe2x80x9d when Y is xe2x80x94SO2xe2x80x94 are: xe2x80x94CH2xe2x80x94 and xe2x80x94NHxe2x80x94.
Examples of R groups are:
Phenylcarbamoyl,
p-hydroxy-phenylcarbamoyl,
benzylcarbamoyl,
cyclobutylcarbonyl,
2-(m,p-dihydroxyphenyl)-ethylcarbonyl,
2-phenylglycyl,
2-(o-fluorophenyl)glycyl,
N-phenylglycyl,
xcex1-amino-(2-thienyl)acetyl,
3-(4-imidazolyl)acryloyl,
3-(2-furyl)acryloyl,
3-(2-thienyl)acryloyl,
3-(3-indolyl)acryloyl,
3-(4-hydroxyphenyl)acryloyl,
N-(m-aminophenyl)glycyl,
[(1-methyl-1H-tetrazol-5-yl)thio]acetyl,
[(5-methyl-1,3,4-thiadiazol-2-yl)thio]acetyl,
1H-tetrazol-1-ylacetyl,
[1H-benzotriazol-1-yl)thio]acetyl, tyrosyl,
2-(p-hydroxyphenyl)glycyl,
2-(m-hydroxyphenyl)glycyl,
2-(m,p-dihydroxyphenyl)glycyl, tryptophanyl,
t-butoxycarbonyl,
3-pyridylacetyl,
benzyloxycarbonyl,
2-(2-amino-4-thiazolyl)glycyl,
2-amino-4-thiazolglyoxyloyl,
xcex1-hydroxy-phenylacetyl,
xcex1-(sulphonyloxy)-phenylacetyl,
3-xcex1-acetamidocinnamoyl,
2-carboxy-2-(3-thienyl)acetyl,
2-indolylcarbonyl,
2-(R,S)-2-oxo-3-tetrahydrothienyl-carbamoyl,
2-(R)-2-oxo-3-tetrahydrothienyl-carbamoyl,
2-(S)-2-oxo-3-tetrahydrothienyl-carbamoyl.
The compounds of formula I can be divided into two sub-groups, namely into bicyclic compounds having the formula 
in which R is defined above, R10 represents hydrogen, halogen, carbamoyloxy, lower alkanoyloxy or a group of the formula xe2x80x94Sxe2x80x94Het, wherein Het represents a 5- or 6-membered heteroaromatic group, and R30 represents hydrogen or R10 and R30 together represent a group having the formula
xe2x95x90CHxe2x80x94Raxe2x80x83xe2x80x83(c)
wherein Ra signifies one of the groups
xe2x80x94CORbxe2x80x83xe2x80x83(c1)
xe2x80x94CH2xe2x80x94OCORcxe2x80x83xe2x80x83(c2)
xe2x80x94CH2xe2x80x94NRdRexe2x80x83xe2x80x83(c3)
xe2x80x94CH2xe2x80x94Sxe2x80x94Hetxe2x80x83xe2x80x83(c4)
in which Rb represents alkoxy or amino, Rc represents lower alkyl, phenyl or amino, Rd and Re each independently represent hydrogen or lower alkyl or Rd and Re together with the N atom to which they are attached represent a 5- or 6-membered N-heterocycle which optionally contains a further nitrogen, oxygen or sulphur atom and Het represents a 5- or 6-membered heteroaromatic group containing nitrogen, sulphur and/or oxygen, and their pharmaceutically compatible salts, and into tricyclic compounds having the formula 
in which R and A are defined above, and their pharmaceutically compatible salts.
The residue which is usable in the 3-position of cephalosporin antibiotics and which is defined as A can represent any of the conventional 3-substituents which are well known to those of ordinary skill in the art of cephalosporin antibiotics, for example, hydrogen, methyl, methoxy, chlorine or a group xe2x80x94CH2L in which L signifies the residue of a nucleophilic compound. As L residues there come into consideration, for example: acetoxy, carbamoyloxy or residues of the formula 
wherein R4 represents hydrogen or carbamoyl, or a group xe2x80x94SR5 in which R5 is an optionally substituted 5- or 6-membered heterocycle with 1-4 hetero atoms, for example, oxygen, sulphur, selenium and/or nitrogen. Tetrazolyl, triazolyl, thiadiazolyl and triazinyl are just some of the many examples of R5. These residues can also be substituted, for example, by lower alkyl such as methyl or ethyl, by halogen such as chlorine, fluorine or bromine, by hydroxy or oxo groups. The 1,2,4-triazol-3-yl, 1-methyl-tetrazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3yl, 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl, 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl, and 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-2-yl groups are examples of such substituted residues. Other examples can be found in Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972).
Objects of the present invention are xcex2-lactams of formula I above and pharmaceutically compatible salts thereof and as pharmaceutically active substances, the manufacture of these compounds and intermediates for the manufacture of these compounds, medicaments containing a compound of general formula I or pharmaceutically compatible salts thereof and the manufacture of such medicaments as well as the use of compounds of general formula I and of pharmaceutically compatible salts thereof in the control or prevention of illnesses in mammals, both human and non-human.
Of the compounds of formula I in which R represents lower alkoxycarbonyl there are preferred those in which R represents t-butoxycarbonyl and their pharmaceutically compatible salts. t-Butoxy (1S,5R)-7-oxo-6-sulpho-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate and (1aS,3aR,6bR)-1,1a,3a,6b-tetrahydro-5-methoxy-1-oxo-2,6a-diazacyclobuta[cd]indene-2,6(3H,4H)-dicarboxylic acid 2-t-butyl monoester and their pharmaceutically compatible salts are especially preferred.
Further preferred compounds of formula Ia are:
(1S,5R)-7-Oxo-2-(phenylcarbamoyl)-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-(benzylcarbamoyl)-7-oxo-6-sulpho-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-7-oxo-2-(N-phenylglycyl)-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-cyclobutylcarbamoyl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-7-oxo-2-(R,S)-(2-oxo-3-tetrahydrothienylcarbamoyl)-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-7-oxo-2-(R)-(2-oxo-3-tetrahydrothienylcarbamoyl)-2,6-diazabicyclo[3 .2.0]heptane-6-sulphonic acid,
(1S,5R)-2-(4-hydroxyphenylcarbamoyl)-7-oxo-2,6-diazabicyclo[3 .2.0]heptane-6-sulphonic acid,
and their pharmaceutically compatible salts.
Of the compounds of formula I in which R represents the acyl residue of an xcex1-amino acid there are preferred those having the formula 
in which RO represents the acyl residue of an xcex1-amino acid having the formula 
wherein Q1 signifies a 5- or 6-membered (hetero)aromatic ring which optionally contains a nitrogen, sulphur and/or oxygen atom and which is optionally bonded with a further fused phenyl ring and n signifies the number 0 or 1,
and their pharmaceutically compatible salts. With regard to Q1, see the discussion hereinabove concerning Q as a 5- or 6-membered (hetero)aromatic ring which optionally contains a nitrogen, sulphur and/or oxygen atom.
Especially preferred groups under group (c) are those of the formula 
in which X represents hydrogen, hydroxy or fluorine and m represents the number 1 or 2.
Especially preferred groups Q1 in groups (c) and, respectively, (c1) are phenyl, thienyl, p-hydroxyphenyl, m-hydroxyphenyl, m,p-dihydroxyphenyl, o-fluorophenyl, m-fluoro-p-hydroxyphenyl, o-fluoro-p-hydroxyphenyl, indolyl and 2-amino-4-thiazolyl.
Preferred compounds of formula Ic containing group (c) are:
(1S,5R)-7-Oxo-2-L-tyrosyl-2,6diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-7-oxo2-L-tryptophanyl-2,6diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[(R or S)-xcex1-amino-(2-thienyl)acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[DL-2-(2-amino-4-thiazolyl)glycyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid
and pharmaceutically compatible salts of these compounds.
Especially preferred compounds containing group (c1) are:
(1S,5R)-7-Oxo-2-(D-2-phenylglycyl)-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-7-oxo-2-(L-2-phenylglycyl)-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[D-2-(p-hydroxyphenyl)glycyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[R-2-(m-hydroxyphenyl)glycyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[DL-2-(m-hydroxyphenyl)glycyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[DL-2-(o-fluorophenyl)glycyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[(R,S)-amino-(3,4-dihydroxy-phenyl)acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid
and pharmaceutically compatible salts of these compounds.
Of the compounds of formula Ia in which R signifies a residue (a) of the formula Qxe2x80x94Xxe2x80x94Yxe2x80x94 there are preferred those having the formula 
in which Roo represents a group of the formula
Q2xe2x80x94CHxe2x95x90CHCOxe2x80x94xe2x80x83xe2x80x83(d)
wherein Q2 signifies a phenyl ring or a 5- or 6-membered heteroaromatic ring which contains nitrogen, sulphur and/or oxygen and which is optionally bonded with an existing phenyl ring,
and their pharmaceutically compatible salts.
Preferred compounds of formula Id containing group (d) are:
(1S,5R)-2-[(E)-3-(2-furyl)acryloyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[(E)-3-(3-indolyl)acryloyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[(E)-3-(4-imidazolyl)acryloyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[(E)-3-(2-thienyl)acryloyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-(E)-2-[3-(4-hydroxyphenyl)acryloyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid
and their pharmaceutically compatible salts.
Further preferred compounds of formula Ia in which R signifies a residue of the formula Qxe2x80x94Xxe2x80x94Yxe2x80x94 are compounds having the formula 
in which Rooo represents a group of the formula
Q3(S)nxe2x80x94CH2COxe2x80x94xe2x80x83xe2x80x83(e)
wherein n signifies 0 or 1 and Q3 signifies a phenyl ring or a 5- or 6-membered N-heterocycle which optionally contains sulphur, which is optionally substituted by lower alkyl or amino and which is optionally bonded with a fused phenyl ring,
and their pharmaceutically compatible salts.
Preferred compounds of formula Ie containing group (e) are:
(1S,5R)-2-[[(1-Methyl-1H-tetrazol-5-yl)thio]acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[[1H-benzotriazol-1-yl)thio]acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[[(5methyl-1,3,4thiadiazol-2-yl)thio]acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-7-oxo-2-(1H-tetrazol-1-ylacetyl)-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[(2-isopropyl-2H-tetrazol-5-yl)-acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid
and their pharmaceutically compatible salts.
The following are further compounds of formula Ia in which R signifies a residue of the formula Qxe2x80x94Xxe2x80x94Yxe2x80x94
Benzyl (1S,5R)-7-oxo-6-sulpho-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate,
(1S,5R)-2-[(Z)-3-xcex1-acetamidocinnamoyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(R/S)-xcex1-(1S,5R)-2-[2-carboxy-2-(3-thienyl)acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-7-oxo-2-(3-pyridylacetyl)-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[(R,S)-2-indolylcarbonyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
(1S,5R)-2-[(R)-xcex1-hydroxyphenylacetyl]-7-oxo-2,6-diazabicyclo[3.4.0]heptane-6-sulphonic acid,
(1S,5R)-2-[(S)-xcex1-hydroxyphenylacetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid,
R(xcex1)-[[(1S,5R)-7-oxo-6-sulfo-2,6-diazabicyclo[3.2.0]hept-2-yl]carbonyl]benzyl sulphate,
(1S,5R)-2-(2-amino-4-thiazolglyoxyloyl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulphonic acid
and pharmaceutically compatible salts of these compounds.
The xcex2-lactams of formula I in accordance with the invention as well as their pharmaceutically compatible salts can be manufactured in accordance with the invention by
(a) treating a compound having the formula 
in which R1, R2 and R3 have the significance given above, with agents yielding the residue R, or
(b) for the manufacture of a compound of formula I in which R contains a free amino group or hydroxy group(s), cleaving off the amino protecting group or hydroxy protecting group(s) in a compound having the formula 
in which R1, R2 and R3 have the significance given above and Rf represents a residue defined under R having a protected amino group or hydroxy group(s),
or
(c) for the manufacture of a compound of formula I in which R1 and R2 are different from group (b), treating a compound having the formula 
in which R has the significance given above, R10 represents hydrogen, halogen, carbamoyloxy, lower alkanoyloxy or a group of the formula xe2x80x94Sxe2x80x94Het, wherein Het represents a 5- or 6-membered heteroaromatic group, and R30 represents hydrogen or R10 and R30 together represent a group of the formula
xe2x95x90CHxe2x80x94Raxe2x80x83xe2x80x83(c)
wherein Ra signifies one of the groups
xe2x80x94CORbxe2x80x83xe2x80x83(c1)
xe2x80x94CH2xe2x80x94OCORcxe2x80x83xe2x80x83(c2)
xe2x80x94CH2xe2x80x94NRdRexe2x80x83xe2x80x83(c3)
xe2x80x94CH2xe2x80x94Sxe2x80x94Hetxe2x80x83xe2x80x83(c4)
in which Rb represents lower alkoxy or amino, Rc represents lower alkyl or amino, Rd and Re each represent hydrogen or lower alkyl or Rd and Re together with the N atom represent a 5- or 6-membered saturated N-heterocycle which optionally contains a further nitrogen, oxygen or sulphur atom and Het represents a 5- or 6-membered heteroaromatic group containing nitrogen, sulphur and/or oxygen,
with an agent yielding the sulpho group SO3H, or
(d) for the manufacture of a compound of formula I in which R1 and R2 together represent the group (b) defined above, reacting a compound having the formula 
in which R and A have the significances given above and R6 represents a carboxylic acid protecting group,
with agent which cleave the carboxylic acid protecting group R6, or
(e) for the manufacture of a pharmaceutically compatible salt of a compound of formula I, converting a compound of formula I into such a salt.
The following procedures can be used for the introduction of the R residue into starting materials of formula II in accordance with variant (a) of the process in accordance with the invention:
(a1) When R contains a terminal carbonyl group or thiocarbonyl group, a compound of formula II is acylated with an acid of the formula ROH or with one of its reactive derivatives. As acylating agents there come into consideration: corresponding acids of the formula ROH in the presence of 2-halopyridinium salts, for example, of 2-chloro- or 2-fluoro-1-methylpyri-dinium chloride or tosylate, or also in the presence of N,Nxe2x80x2-dicylclohexylcarbodimide or carbonyldiimidazole, the latter preferably together with N-hydroxybenzotriazole, N-hydroxy-succinimide or N-hydroxyphthalimide. There can also be used corresponding, reactive derivatives of the carboxylic acid such as for example, the acid halide (preferably the chloride), acid anhydride or acid azide. The corresponding thiol esters such as for example, 2-benzthiazolyl thioesters as well as hydroxybenztriazole esters, N-hydroxysuccinimide esters or N-hydroxyphthalimide esters can also be used. The reaction is preferably carried out in an organic solvent or solvent mixture, optionally in admixture with water, for example, acetone, methylene chloride, tetrahydrofuran, dioxan, dimethylacetamide, dimethylformamide or acetonitrile, optionally in admixture with water. The temperature generally lies between xe2x88x9230xc2x0 C. and room temperature.
(a2) When R contains a terminal sulphonyl group, a compound of formula II is sulphonated with an acid of the formula ROH or with one of its reactive derivatives. Sulphonic acid halides, especially the chlorides, primarily come into consideration as sulphonating agents. In other respects, the reaction is effected essentially as above under (a1).
(a3) When R contains a terminal xe2x80x94CONHxe2x80x94 group, a compound of formula II is reacted with a corresponding substituted 3-phenyloxaziridine of the formula 
in which R7 represents lower alkoxy or the group Qxe2x80x94Xxe2x80x94 wherein Q and X have the above significance.
Solvent and temperature range are essentially as above under (a1).
Where the group Qxe2x80x94Xxe2x80x94 is to be introduced, a starting material of formula XLV in which R7 represents lower alkoxy, especially methoxy, is preferably used. The resulting product of the formula 
in which R1, R2 and R3 have the above significance and R70 represents lower alkoxy,
is hydrolyzed and decarboxylated with a base, for example, potassium hydroxide in aqueous tetrahydrofuran at room temperature. The resulting intermediate of the formula 
in which R1, R2 and R3 have the above significance, is acylated with an acid of the formula Qxe2x80x94Xxe2x80x94COOH or with one of its reactive derivatives in accordance with the details under (a1) above.
Acids of the formula ROH, which contain amino groups, are preferably protected at the amino group, for example, by benzyloxycarbonyl, t-butoxycarbonyl or chloroacetyl. Corresponding compounds of formula If obtained after the acylation are converted in accordance with the invention according to process variant (b) into end products having a free amino group by cleavage of the amino protecting group. The liberation of the amino group is effected in a manner well known to those of ordinary skill in the art, for example, by hydrogenation with palladium/charcoal or treatment with palladium/charcoal and 1,4-cyclohexadiene in an organic solvent such as ethanol at about 0 to 80xc2x0 C. (benzyloxycarbonyl); with trifluoroacetic acid, optionally in the presence of anisole, or with hydrogen chloride in an organic solvent such as dioxan at about xe2x88x9220 to 0xc2x0 C. (t-bubutoxycarbonyl); or with thiourea in a polar solvent, preferably in water at neutral pH, and about 0 to 30xc2x0 C. (chloroacetyl).
Where a product of formula I in which R contains two vicinal hydroxy groups is to be manufactured, these hydroxy groups in the corresponding starting material of the formula ROH can be protected; the hydroxy groups are liberated after the reaction has been carried out.
Preferred protection is by diphenylmethyl (for example a 3,4-dihydroxyphenyl group is then converted into the 2,2-diphenyl-1,3-benzodioxol-5-yl group) by heating with diphenyldichloromethane. The cleavage of the diphenylmethyl group is preferably effected by the action of an acidic agent in a trace of water, for example, by concentrated aqueous hydrochloric acid or, especially, by trifluoroacetic acid with a trace of water. The reaction temperature is suitably 0xc2x0 C. to about room temperature. If desired, this cleavage can also be carried out by hydrogenation with palladium-charcoal in an inert organic solvent, for example, methanol, ethanol, tetrahydrofuran or ethyl acetate, at a temperature between about 0xc2x0 C. and 80xc2x0 C.
The hydroxy groups can also be protected by lower alkanoyl groups, for example, acetyl. Introduction is for example, by treatment with a lower alkanoyl halide or anhydride, for example, the chloride, in the presence of a base such as sodium hydroxide, DBU or diisopropylethylamine. The cleavage is effected under mild alkaline conditions (pH about 7-8), for example, with sodium hydroxide or carbonate, at about 0xc2x0 C. to 50xc2x0 C.
A further possibility of protecting the hydroxy groups is the use of silyl groups, for example, trimethylsilyl and t-butyldimethylsilyl. These are advantageously introduced by treatment with the corresponding silyl chloride. The cleavage can be effected by the action of a fluoride, preferably tetrabutylammonium fluoride, in an organic solvent, for example, acetonitrile, at about 0xc2x0 C. to 50xc2x0 C.
According to variant (c) of the process in accordance with the invention a compound III is sulphonated. The sulphonation can be effected in a manner known per se by reaction with sulphur trioxide or a reactive derivative thereof, for example, with complexes of sulphur trioxide and an organic base such as pyridine, dimethylformamide, picoline etc. The reaction is effected for example, at about xe2x88x9220 to +80xc2x0 C. in an inert organic solvent, for example, in an ether such as dioxan, in an ester such as ethyl acetate, in a chlorinated hydrocarbon such as methylene chloride; in acetonitrile, dimethylformamide or pyridine.
Ester protecting groups of the esters of formula IV used according to variant (d) of the process in accordance with the invention are preferably those which can be transformed into the free carboxy group under mild conditions, for example, t-butyl, p-nitro- benzyl, benzyl, benzhydryl, allyl, etc. The ester protecting groups are cleaved off for example, as follows: benzyl and p-nitrobenzyl by hydrogenation over palladium/charcoal at about 0xc2x0 C. to 80xc2x0 C. in an organic solvent such as ethyl acetate or methanol or in water or by hydrolysis in the presence of sodium sulphide at (or below) 0xc2x0 C. to room temperature in a solvent such as for example, dimethylformamide (preferably aqueous); t-butyl by treatment with aqueous hydrochloric acid or by reaction with trifluoroacetic acid in the presence of anisole at about 0xc2x0 C. to room temperature with or without additional solvent such as for example, methylene chloride; allyl by palladium-(O)-catalyzed transallylation in the presence of the sodium or potassium salt of 2-ethylcaproic acid, see for example, J. Org. Chem., 1982, 47, 587.
The following Reaction Schemes I-IV illustrate the process for the manufacture of the products in accordance with the invention and, respectively, of the intermediates which occur in the syntheses. 
The symbols in Schemes I through IV have the following significances:
X=hydrogen or tetrahydropyranyl
THP=tetrahydropyranyl
Ms=methanesulphonyl
Y=hydrogen or [(1-imidazolyl)thiocarbonyl]oxy
Rz=benzyloxycarbonyl or t-butoxycarbonyl
Z=benzyloxycarbonyl
BOC=t-butoxycarbonyl
Ø=phenyl
R, Ra, Rb,
Rc, Rd, Re=the meaning given above in formula I
DMB=3,4-dimethoxybenzyl or 2,4-dimethoxybenzyl
pNO2Bz=p-nitrobenzyl
TBDMS=t-butyl-dimethylsilanyl
KW4=reversal of configuration in the 4-position (see hereinafter)
R11=carbamoyloxy or lower alkanoyloxy
R12=Hal, xe2x80x94Sxe2x80x94Het (Het has the above significance).
Scheme I describes the preparation of compounds VIII with Rz=benzyloxycarbonyl (=compounds VIIIa). The preparation of compounds VIII with Rz=t-butoxycarbonyl proceeds in exactly the same manner.
Further details concerning the preparation of starting materials II, If, III and IV used in accordance with the invention will be evident from the following working Examples. In Scheme II the intermediate XVIIa can be prepared with sodium borohydride in analogy to Example 16. For brevity, formulae XIX-XXVI have been drawn with a solid line () in the 4-position, with the corresponding isomer being obtained depending on whether the 4(S)-hydroxy compound XVII or the 4(R)-hydroxy compound XVIIa has been used, whereby the intermediates XX and XXI with a reversal of configuration in the 4-position result (denoted by xe2x80x9cRC 4xe2x80x9d in Scheme II). For the rest, the intermediates XX are prepared for example, by reaction with an isocyanate, for example, chloroacetyl isocyanate, followed by cleavage of the chloroacetyl group with a base such as potassium hydroxide (R11=carbamoyloxy) or by reaction with the corresponding anhydride such as acetic anhydride (R11=lower alkanoyloxy).
In Scheme III the intermediate XXIX can be prepared by treating the ester XXVIIIa with sodium borohydride. The product XXIX can be reacted with for example, mesyl chloride, whereby the product XXX results. By reacting the product XXIX with a lower alkanoyl chloride or an isocyanate (for example, chloroacetyl isocyanate), followed by cleavage of the chloroacetyl group with a base there are obtained products XXXI, and by reacting product XXX with the corresponding amine or heterocyclic thiol in the presence of a base there result products XXXII and, respectively, XXXIII. The products XXVIII, XXXI, XXXII and XXXIII can all be converted into corresponding end products XXXV by cleavage of the 6-protecting group and sulphonylation. The group Z cannot be removed without saturating the double bond in the 4-position and, therefore, when an end product having another residue R in position 2 is desired, the corresponding 2-BOC-protected compound (obtainable for example, by removing Z by hydrogenation and reaction with t-butoxycarbonyl anhydride) need be used in place of the Z-protected intermediate XVII.
As mentioned earlier, the compounds of general formula I in accordance with the invention and pharmaceutically compatible salts thereof with bases exhibit pronounced xcex2-lactamase- inhibiting activities against xcex2-lactamases from various bacterial strains as found in mammals. As illustrated hereinafter, these therapeutically valuable properties can be determined in vitro on isolated xcex2-lactamases:
A. Isolation of the xcex2-lactamases
Various xcex2-lactamases can be isolated from penicillin- or cephalosporin-resistant bacterial strains such as Klebsiella pneumoniae NCTC 418, Proteus vulgaris 1028, Bacillus licheniformis 749/C, Escherichia coli SN01 and Citrobacter freundii 1203. For this purpose, the corresponding strains are cultivated in Tryptic Soy Broth (Difco) and harvested by centrifugation in the last logarithmic growth phase (when necessary 50-100 mg/l of ampicillin are added to the medium towards the end of the log-phase in order to induce the xcex2-lactamase). The thus-obtained bacterial mass is treated with 20 mM Tris-HCl buffer (pH 7.0); the cells are broken open with a French press while cooling. The mixture is centrifuged (20,000 r/min.) for 20-30 minutes and a clear crude extract is obtained. The purification of the proteins is effected according to the methods of Cartwright, S. J. and Waley, S. G. [Biochem J. 221, 505-512 (1980)] and, for B. licheniformis, Ellerby, L. M. et al. [Biochemistry, 29, 5797-5806 (1990)].
B. Determination of the xcex2-lactamase activity
The determination of the activity of the isolated xcex2-lactamases can be carried out according to the method of O""Callaghan, C. H. et al. [Antimicr. Ag. Chemother., 1, 283-288 (1972)] using the chromogenic cephalosporin nitrocefin (87/312 from Glaxo). The requisite test batch contains per ml of water: 50 mM phosphate buffer (pH 7.0), 0.1 mM nitrocefin and sufficient enzyme (xcex2-lactamase) to achieve a xcex94A/min. of about 0.1. The cleavage of the substrate, which is accompanied by a change in colour, is effected at 37xc2x0 C. and is followed quantitatively at 482 nm using a spectral photometer.
C. Determination of the xcex2-lactamase-inhibiting activity of the compounds of general formula I
The above-described cleavage of the chromogenic substrate by xcex2-lactamases (test B.) can be inhibited by the addition of compounds of general formula I (inhibitors). Since it has been found that the inhibitors irreversibly inactivate the xcex2-lactamase in a time-dependent reaction, the reaction (cleavage of the substrate) is in each case started by addition of the substrate after a pre-incubation period of xcex2-lactamase with inhibitor of 15 minutes. As a measurement for the affinity of the particular tested inhibitor to the xcex2-lactamase, which is a measurement of the strength of the inhibitor, there serves that concentration which inhibits by 50% (IC 50 in nM) the cleavage of the substrate (nitrocefin) effected under the above test conditions (test B) in the absence of an inhibitor. 4 to 6 tests with different concentrations of inhibitor were carried out in order to determine the IC50. The determination of the IC50 was effected by means of a graph.
The results obtained in the above test (test C) are presented in Table I hereinafter.
(Test organism: Citrobacter freundii)
The IC50 value in nM is given for the end products of the following working Examples. This is a measurement of the xcex2-lactamase inhibition. An IC50 value of 1000 nM or less is considered to be significant.
D. Determination of the xcex2-lactamase-inhibiting activity by combination of a compound of general formula I with ceftriaxone
The minimum inhibitory concentration in vitro (MIC in xcexcg/ml) of a 1:4 combination of ceftriaxone with a compound of formula I against Citrobacter freundii is measured and compiled in Table 2 hereinafter.
The products in accordance with the invention can be used as medicaments, for example, in the form of pharmaceutical preparations which contain them or their salts in admixture with a pharmaceutical, organic or inorganic inert carrier material which is suitable for parenteral or enteral administration, such as for example, water, gelatine, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, Vaseline, etc. The pharmaceutical preparations can be present in solid unit dosage form, for example, as tablets, dragees, suppositories, capsules; or in liquid unit dosage form, for example, as solutions, suspensions or emulsions. They may be sterilized and/or may contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure, anaesthetics or buffers, the types and the use of which are well known to those of ordinary skill in the art. The compounds of formula Ia and their salts preferably come into consideration for parenteral administration and, for this purpose, are preferably prepared as lyophilizates or dry powders for dilution with usual agents such as water or isotonic saline. The compounds of formula Ib and their salts as well as the compounds of formula Ic in which Ro represents group (c1) come into consideration for parenteral administration and also for enteral administration in the appropriate unit dosage forms well known in the art.
As mentioned earlier, the compounds of formula I and their pharmaceutically compatible salts can be used in accordance with the invention in the control or prevention of illnesses in mammals, human and non-human, especially in the control of xcex2-lactamase-forming pathogens in combination with xcex2-lactam antibiotics, that is antibiotics which contain a xcex2-lactam ring, for example penicillins such as benzylpenicillin, piperacillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, tricarcillin, ampicillin, amoxycillin or mecillinam and cephalosporins such as ceftriaxone, ceftazidime, cefetamet, cefatamet pivoxil, cefotaxime, cefmenoxime, ceftizoxime, cefuroxime, cephaloridine, cephalotin, cefazolin, cephalexin, cefoxitin, cephacetrile, cefamandole, cephapirin, cephradine, cephaloglycine, (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-(azidomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid or (E)-2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-(azidomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate. Thereby, the compounds of formula I or pharmaceutically compatible salts thereof with bases can be administered before, simultaneously with or after the administration or intake of xcex2-lactam antibiotics. Where the products in accordance with the invention are administered simultaneously with a xcex2-lactam antibiotic, then this can be effected by administration as an ad-hoc combination or in the form of a pharmaceutical combination which contains a compound of formula I or a pharmaceutically compatible salt thereof with a base and a xcex2-lactam antibiotic; such pharmaceutical combinations are also an object of the present invention.
The dosage of the compounds of formula I and of the pharmaceutically compatible salts thereof with bases can vary within wide limits and will, of course, be fitted in each particular case to the individual requirements and to the xcex2-lactamase-producing pathogen to be controlled. In general, a daily dosage of about 0.1 to about 2.0 g should be appropriate. The ratio of xcex2-lactamase inhibitor (compound of formula I or pharmaceutically compatible salt thereof with a base) to xcex2-lactam antibiotic can also vary within wide limits and will be fitted to the individual requirements in each particular case. In general, a ratio of about 1:20 to about 1:1 should be appropriate.
As mentioned earlier, medicaments containing a compound of formula I or a pharmaceutically compatible salt thereof are also an object of the present invention, furthermore also a process for the manufacture of such medicaments which is characterized by bringing one or more compounds of formula I or pharmaceutically compatible salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form; in this connection reference is again made to the pharmaceutical combinations referred to above, which are also an object of the present invention. In particular, pharmaceutical combinations containing a compound of formula I or a pharmaceutically compatible salt thereof and a xcex2-lactam antibiotic, for example, a penicillin such as benzylpenicillin, piperacillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, tricarcillin, ampicillin, amoxycillin or mecillinam or a cephalosporin such as ceftriaxone, ceftazidime, cefetamet, cefatamet pivoxil, cefotaxime, cefmenoxime, ceftizoxime, cefuroxime, cephaloridine, cephalotin, cefazolin, cephalexin, cefoxitin, cephacetrile, cefamandole, cephapirin, cephradine, cephaloglycine, (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-3-(azidomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid or (E)-2-(isobutoxycarbonyl)-2-pentenyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-(azidomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, are an object of the present invention. Such combinations are suitable for the control of xcex2-lactamase-forming pathogens.
The following abbreviations are used in the Examples hereinafter, which illustrate the present invention in more detail, but are not intended to limit its extent in any manner: DMF signifies dimethylformamide, THF signifies tetrahydrofuran, AIBN signifies xcex1,xcex1xe2x80x2-azo-isobutyronitrile, DCC signifies dicyclohexylcarbodiimide, HOBT signifies 1-hydroxybenzotriazole and DMSO signifies dimethyl sulphoxide. All temperatures are in degrees Celcius unless otherwise stated.